Traumatic Brain Injury (TBI) is a major health issue. After the primary injury, there is substantial secondary injury attributable to infiltrating immune cells, cytokine release, reactive oxygen species, excitotoxicity, and other mechanisms. Despite many preclinical and clinical trials designed to limit such secondary damage, no successful therapies have emerged. However, we have found that Immune-modifying nanoParticles (IMP) are a strong candidate for a clinically translatable acute pharmacologic intervention for TBI. IMP are highly negatively charged, 500 nm-diameter particles composed of the FDA-approved biodegradable biopolymer, carboxylated poly(lactic-co-glycolic) acid (PLGA-COOH). After intravenous (IV) administration, IMP bind to the macrophage receptor with collagenous structure (MARCO) on monocytes. Monocytes bound to IMP no longer travel to sites of inflammation, but instead are sequestered in the spleen. Because IMP specifically target the MARCO+ subset of monocytes, it is distinctly different from other approaches that non-specifically target all monocyte/macrophage lineage cells including microglia. IV treatment with IMP in two different TBI models profoundly reduced the number of immune cells infiltrating into the brain, mitigated the inflammatory status of the infiltrating cells, and reduced levels of an array of cytokines and chemokines. More importantly, IMP treatment resulted in attenuated edema, preservation of brain tissue, and significant preservation of both physiologic visual and motor function. The proposed studies will examine IMP-mediated changes in gene expression that alter the inflammatory status of infiltrating cells, limit gliosis, reduce edema, and promote neuronal survival. They also will examine effects of IMP on other cell types including microglia, progenitor cells, and other immune cells. Notably, IMP are made of an FDA-approved material that is stable at room temperature and could easily be given immediately IV after TBI in the field by EMTs or in the emergency room. Mechanistically the proposed studies will help to understand more clearly the effects of infiltrating hematogenous monocyte-derived macrophages after TBI. Significantly, they also will help to develop a potentially effective and practical therapy for human TBI.